Covalent inhibitors of HECT and RBR E3 ligases

Covalent inhibitors of HECT and RBR E3 ubiquitin ligases represent a modality targeting enzymes responsible for the transfer of ubiquitin to substrate proteins. HECT (Homologous to E6AP C-Terminus) and RBR (RING-between-RING) E3 ligases are subfamilies characterized by catalytic cysteine residues that form transient thioester bonds with ubiquitin prior to substrate modification. Inhibitors act by covalently binding these cysteines, irreversibly blocking the ubiquitin transfer process. These enzymes play critical roles in protein turnover, cell cycle regulation, apoptosis, and DNA repair, and are implicated in diseases such as cancer and neurodegeneration. "RCR" is not a standard recognized E3 family in the field. Thus, while this pharmacologic approach addresses valid therapeutic targets, the entry itself is conceptually overbroad and partly inaccurate, bundling multiple distinct enzyme families and including a potentially mistaken term.

Other names

HECT-type E3 ligaseRBR-type E3 ligaseE3 ubiquitin-protein ligase

Covalent binding to the active-site cysteine, inactivating E3 ligase activity and preventing ubiquitin transfer